WO2010058314A1 - Hydroxyquinolin-2(1h)-ones et leurs dérivés - Google Patents

Hydroxyquinolin-2(1h)-ones et leurs dérivés Download PDF

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Publication number
WO2010058314A1
WO2010058314A1 PCT/IB2009/054925 IB2009054925W WO2010058314A1 WO 2010058314 A1 WO2010058314 A1 WO 2010058314A1 IB 2009054925 W IB2009054925 W IB 2009054925W WO 2010058314 A1 WO2010058314 A1 WO 2010058314A1
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Prior art keywords
hydroxy
fluoro
chloro
oxo
hydroxyquinolin
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PCT/IB2009/054925
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English (en)
Inventor
Allen Jacob Duplantier
Xinmin Gan
Lain-Yen Hu
Jiemin Lu
Susan Mary Kult Sheehan
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Pfizer Inc.
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Publication of WO2010058314A1 publication Critical patent/WO2010058314A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds useful for the treatment of cognitive-related disorders and neuropathic pain disorders in a mamma l e.g. , a human.
  • the invention also relates to pharmaceutical compositions containing such compounds.
  • DAAO D-amino acid oxidase
  • NMDA N-methyl-D-aspartate
  • Small organic molecules which inhibit the enzymatic cycle of DAAO, may control the levels of D-serine, and thus influence the activity of the NM DA receptor in the brain.
  • NMDA receptor activity is important in a variety of disease states , such as schizophrenia, psychosis, ataxias, ischemia, several forms of pain including neuropathic pain, and deficits in memory and cognition.
  • Neurodegenerative d iseases are d iseases in which central nervous system (CNS) neurons a nd/or peripheral neurons undergo a progressive loss of function, usually accompanied by (and perhaps caused by) a physica l deterioration of the structure of either the neuron itself or its interface with other neurons .
  • CNS central nervous system
  • Such cond itions include Parkinson's d isease, Alzheimer's d isease, Huntington's d isease and neuropathic pain.
  • N-methyl-D-aspartate (NMDA)-glutamate receptors are expressed at excitatory synapses throughout the CNS- These receptors med iate a wide range of brain processes, including syna ptic plasticity, that are associated with certain types of memory formation and learning.
  • NM DA-glutamate receptors require bind ing of two agonists to effect neurotransmission. One of these agonists is the excitatory amino acid L- glutamate, while the second agonist, at the so-called “strychnine-insensitive glycine site", is now thought to be D-serine.
  • D-serine is synthesized from L-senne by serine racemase and degraded to its correspond ing ketoacid by DAAO- Together, serine racemase and DAAO are thought to play a crucial role in modulating N MDA neurotransmission by regulating CNS concentrations of D-serine,
  • DAAO inhibitors are known in the literature including aminopyrazolines such as WO 2007/093829, fused bicyclics such as VVO 2008/089453, WO 2008/005456, WO2007/039773 and US 7 ,1 66,725.
  • the present inventors have now discovered a group of very potent small molecules with selective DAAO inhibitory activity
  • the present invention relates to a method of treating a disorder or cond ition that can be treated by inhibiting D-amino acid oxidase (DAAO) activity in a mammal, preferably a human , in need of such treatment comprising administering to said mammal an effective amount of a compound of formula
  • DAAO D-amino acid oxidase
  • ring "A” is a 6 membered aryl or 5 or 6 membered heteroaryl ring; wherein said 6 membered heteroaryl ring has one nitrogen heteroatom and wherein said 5 membered heteroaryl ring has one or two heteroatoms selected from N, O or S; e ach R is independently selected from the group consisting of hydrogen, chloro, fiuoro, bromo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and cyano (wherein R is a substituent on either ring of the hydroxy quinolinone nucleus); n is an integer selected from the group consisting of zero, one, two or three; or a pharmaceutically acceptable salt thereof.
  • T he present invention further relates to a method of enhancing cognition in a mammal, preferably a huma n, comprising administering to said mammal an effective amount of a compound of formula I
  • Another embod iment of the methods of the invention relates to compounds of the formula I wherein ring "A” is a 6 membered heteroa ry! ring; containing one nitrogen heteroatom.
  • ring "A” is a 5 membered heteroa ryl ring; containing one heteroatom selected from N, O or S
  • ring "A” is a 5 membere ⁇ heteroa ryl ring: containing two heteroatoms wherein the first heteroatom is selected from N , O or S and the second heteroatom is N,
  • the present methods also relates to a group of compounds of formula I wherein said compound is selected from the group consisting of: 6 -ch!oro-3-hyd roxyquino!in-2( 1 H )-one; 3 -hyd r ⁇ xy-6,8-d imethylquin ⁇ lin-2(1 H )- ⁇ ne; 3 -hydroxy-6-methylq ⁇ nohn-2( 1 H )-one;
  • the present invention also relates to the following compounds per se and to the method of using said compounds for the treatment of a disorder or condition that can be treated by inhibiting D-amino acid oxidase (DAAO) activity in a mammal, perf ⁇ rably a human, in need of such treatment:
  • DAAO D-amino acid oxidase
  • An embodiment of the present invention of particular interest relates to the 3-hydr ⁇ xyquin ⁇ lin-2(1H)- ⁇ e compounds:
  • Another embodiment of the present invention of particular interest relates to a group of 6-membered heteroarylfused-pyridin-2(1 H)-ODe compounds selected from the group consisting of.
  • a nother embodiment of the present invention of particular interest relates to the 5-membered heteroarylfused-pyridin-2(1H)-ones:
  • Another embodiment of the present invention of interest to the inventors relates to a group of (5-membered heteroaryifused)-pyr ⁇ din-2(1H)- ones selected from the group consisting of:
  • Another embodiment of the present invention of interest to the inventors relates to a group of (6-membered heteroaryl fused)-pyridin-2(1H ⁇ - ones selected from:
  • a group of particularly interesting 4-fiuoro-(6-membered heteroaryl fused)-pyridin-2(1 H)-ones include:
  • a group of 4-fluoro-6-membered-heteroary! fused pyridin-2(1H)-ones of particular interest include;
  • fluoroquinolin-2(1 H)-ones of interest to the inventors include;
  • Mitriie q ⁇ ino!in-2(1H)-ones of interest to the inventors include:
  • a group of chloro-quinolin-2(1H)-one$ of interest to the present inventors includes: 6 -chloro-3-hydroxy-8-methy!qu ⁇ olin-2(1 H)-one.
  • a group of trifluoro-quinolin-2(1H)-ones of interest to the present inventors includes1 3 -hydroxy-5-(trifluoromethyl)quinolin-2(1H)-one;
  • the phrase "the compounds of the invention” includes the general and specific compounds, including examples d iscussed herein and pharmaceutically acceptable salts thereof. If will aiso be understood that the phrase “compounds of the invention and pharmaceutically acceptable sait(s) thereof aiso encompasses the pharmaceutically acceptable hydrates, solvates, and tautomers of the compounds described herein and below and pharmaceutically acceptable salts thereof.
  • phrases "pharmaceutically acceptable SaIt(S)", as used herein, unless otherwise indicated , includes salts of acidic or basic groups which may be present in the compounds of the present invention.
  • the compounds of the present invention that are basic in nature are capable of form ing a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid add ition salts of such basic compounds are those that form non-toxic acid add ition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobr ⁇ mide, hydroiod ide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, is ⁇ nic ⁇ tinate, acetate, lactate, sa licylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinste, f ⁇ marate, gluconate, giuc
  • the compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in add ition to the acids mentioned above.
  • the invention also relates to base add ition salts of the compounds of the invention.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolamrnonium and other base salts of pharmaceutically acceptable organic amines.
  • Suitable base salts are formed from bases which form non-toxic salts.
  • suitable base salts include the a luminum, arginine, benzathine, calcium, choline, d iethylamine, d iolamme. glycine, lysine, magnesium, meglumine, oiamine, potassium , sod ium, fromefha mine and zinc salts.
  • Hemisaits of acids and bases may also be formed , for example, hemisulphate and hemicalcium salts.
  • suitable salts see Ha nd book of Pharmaceutical Salts:
  • the compounds of the invention may also exist in unsoivated and solvated forms.
  • the compounds of the invention and pharmaceutica lly acceptable salts thereof
  • solvate is used herein to describe a noncovalent or easily reversible combination between solvent and solute, or dispersion mea ns and d isperse phase. It will be undotwithstandingood that the solvate can be in the form of a solid , slurry (e.g., a suspension or d ispersion), or solution.
  • solvents include ethanol , metha nol , propanol , acet ⁇ nitrile, d imethyl ether, d iethyl ether, tetrahydrofuran. methylene chlorid e, and water.
  • 'hydrate' is employed when said solvent is water.
  • a currently accepted classification system for orga nic hyd rates is one that defines isolated site, channel or meta l-ion coordinated hydrates - see
  • isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hyd rates , the water molecules lie in lattice channels where they are next to other wafer molecules , In metai-ion coordinated hydrates, the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independ ent of humid ity. When, however, the solvent or water is weakly bound , as in channel solvates a nd hygroscopic compounds, the water/solvent content will be dependent on humidity and d rying cond itions. In such cases, non-stoichiometry will be the norm.
  • metabolites of compounds of the invention that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include; ( i) where the compound of the invention contains a methyl group, an hyd roxy rnethyi derivative thereof (e.g., -CHs -> --CH2Q ⁇ );
  • the compounds of the invention may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention, Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one taut ⁇ mer predominates, Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
  • the compound 7-fluoro-3-hydroxyquino)irv2(1H)-one (1 ) which is exemplified in Example 1 , may exist in the following tautomeric forms:
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, 2 H. 3 H 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, and 36 Ci, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, Le., ⁇ and carbon-14 , i.e.. '4C, isotopes are particularly preferred for their ease of preparation and detectabiiity.
  • substitution with heavier isotopes such as deuterium, i.e. , 2H can afford certain therapeutic adva ntages resulting from greater metabolic stability, for example increased in vivo ha If- life or red uced dosage requirements and , hence, may be preferred in some circumstances.
  • compositions of the invention relates to compositions comprising a compound of the invention and at least one additional ingredient (hereinafter "the compositions of the invention"). It will be understood that the compositions of the invention will encompass any combination of the compound of the invention and the at least one add itional ingred ient.
  • the at least one add itional ingredient include impurities (e.g.
  • solvent as it relates to the compositions of the invention includes organic solvents (e.g., methanol, etha nol, isopropanol, ethyl acetate, methylene chloride, and tetrahyd rof ⁇ ran ) a nd water.
  • the one or more solvents may be present in a non-stoichiometric amount, e.g ., as a trace impurity, or in sufficient excess to d issolve the compound of the invention.
  • the one or more solvents may be present in a stoichiometric amount, e.g. , 0.5: 1 , 1 : 1 , or 2: 1 molar ratio , based on the amount of compound of the invention.
  • At least one add itional ingred ient that is present in the composition of the invention is an organic solvent.
  • at least one additional ingred ient that is present in the composition of the invention is water.
  • at least one add itional ingred ient that is present in the composition of the invention is a pharmaceutica lly acceptable carrier.
  • At least one additional ingred ient that is present in the composition of the invention is a pharmaceutically acceptable excipient.
  • composition of the invention is a solution .
  • composition of the invention is a suspension.
  • composition of the invention is a solid .
  • the invention relates to a composition comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier.
  • the invention relates to a composition
  • a composition comprising a therapeutically effective amount of the compound the invention as defined above, a pharmaceutically acceptable carrier and , optionally, at least one add itional med icinal or pharmaceutica l agent.
  • the compounds of the invention can be prepa red by one or more of the proceed ures generally described in Schemes 1 to 7 below and in the Examples section.
  • ethyi methoxyacetate prepared by treatment with a base.
  • a base for instance lithium bis(thmethylsilyl)amide or lithium d iisopropylamide.
  • a compound of Formula HI can be reacted with a compound of Formula HI to generate a compound of formula il .
  • the requisite aminoaidehydes IH are often commercially available, or can be prepares in a straightforward manner from r ⁇ late ⁇ materials such as the correspond ing carboxylic acid , carboxylic ester or alcohol a s shown in Scheme 3 below.
  • Substituted isatins can also be used to prepare certain compounds of formula I (i.e. l(a) wherein ring "A” is the fused optionally substituted phenyl rad ical), as depicted in Scheme 2.
  • isatin V ⁇ e.g. , a substituted 1 H-indoie-2,3-d ione wherein R is independently selected from hydrogen, chloro, fluoro, aikyl, trifluoromethyl or alkoxy and n is an integer from zero to three
  • ethyl diazoaeetate and an amine base generally d iethylamine
  • acid generally hydrochloric acid
  • An alternative proceed ure employs ethyl diazoacetate and zinc chloride, as detailed in MJ.
  • n is an integer from zero to three to an alcohol of Formula Vl , wherein ring "A" is an optionally substituted phenyl rad ical or an optionally substituted 5 or 6 membered heteroaryl rad ical: R is hydrogen, (C rC*)alky!, (CrC -)a!koxy, trifluor ⁇ methy! or halo; a nd n is an integer from zero to three can be carried out with numerous reagents known to those skilled in the art; the choice of reagent d epends on what other functionality is present in the molecule. One useful reagent for this transformation is lithium aluminum hyd ride.
  • Aromatic or heteroaromatic ottho-bromo aldehydes can also be used to prepare compounds of Formula I. as outlined in Scheme 4, Scheme 4
  • a compound of Formula Xi wherein ring "A" is an optionally substituted phenyl radical or an optionally substituted 5 or 6 membered heteroaryi radical; R is hyd rogen, (C-rCsJalkyl, (C rC ⁇ Jalkoxy, trifluoromethy! or halo; and n is an integer from zero to three, can be reacted with 2-methoxyacetamide under coupling cond itions similar to those described for synthesis of Formula X above, to afford a compound of Formula XH; see also PJ , Manley and M.T. Bilodea ⁇ , Organic Letters 2004, ⁇ , 2433-2435, Ring closure to a compound of Formula I!
  • romoaldehydes of formula Xl can be prepared from the corresponding carboxylic acid , ester or alcohol, in similar fashion to the chemistry depicted in Scheme 3.
  • reaction of a nitrotoluene of Formula XVi With d iethyl oxalate and sod ium ethoxide provides a compound of Formula XV, which can be protected with ethylene glycol under acid ic conditions, such as with para-toluenesulfonic acid , to give a compound of Formula XIV.
  • Red uction of the nitro group for instance with Raney nickel, tin(lf ) chloride or iron/hyd rochloric acid , is followed by intramolecular cyclization to afford a compound of Formula XIII.
  • Subjection of a compound of Formula XIH to acidic cond itions, generally hyd rochloric acid at temperatures of 60-900C then provides a compound of formula Ia.
  • Introd uction of substituents at the 4-posit ⁇ on of the hyd roxypyridone ring into a compound of Formula I can be effecte ⁇ in several ways, depending on the identity of the 4-subst ⁇ tuent. as shown in Scheme 6.
  • a compound of Formula l (b) can be prepared from the aminoketone of Formula XVi H , in s manner analogous to preparation from aminoaldehyde of
  • 4-Fluoro compounds of the formula 1 (C) can be generated from the correspond ing trifluoromethyl starting materia l of Formula XX, following the general method of A.S. Kiselyov et a!., Organic Letters 2004, 6, 4061 -4063.
  • reaction with a compound of Formula XX provides fiuoro-substituted intermed iate of Formula XIX, which is then transformed into a compound of Formula l(c).
  • Introd uction of substituents on the fused aryl or heteroa ryl ring can be effected after preparation of compounds of formula I (and Ia , Ib, Ic and Id ) as described herein above and in the Examples describee herein below by using a protecting group for the alpha-hyd roxy carbonyl system, as shown in Scheme 7,
  • bromine by a cyano group can be effected through pallad ium-catalyzed cyanation; see J . Ramna uth et al.. Synlett 2003, 2237-2239 and references cited therein .
  • the bromine substftuent can be replaced by methyl or ethyl through a Negishi-type coupling with d imethylzinc or d iethylzinc. according to the general proceed ure of J ⁇ 1 Herbert, Tetrahedron Letters 2004, 45, 817-819.
  • Introd uction of an aldehyde can be carried out by lithium-halogen exchange using an organolithium reagent such as n-butyllrthium or ferf-butyllithium, followed by reaction with dimethylformamide.
  • organolithium reagent such as n-butyllrthium or ferf-butyllithium
  • Compounds of the Formula XXI can then be converted to the compound of Formula I, wherein one R is -CN . methyl , Ethyl and -CHO by deproteciion using, for exa mple, boron iribromide or an acid such as hydrochloric acid .
  • Introd uction of functional groups onto the phenyl ring of compound of Formula I can also be accomplished in the absence of a bromine. Nitration of the aryl or heteroary! ring in a compound of Formula XXI is earned out, for instance through reaction with nitric acid and sulfuric acid . Conversion of the nitro group to a halogen atom can be effected through reduction of the ⁇ stro group Xo an amino group, followed by, for exa mple, d iazotization and subsequent Sandmeyer reaction to provide a compound of Formula XXI, wherein one of said R is chlorine or bromine.
  • the compounds of the invention are useful for treating d isorders in a patient such as a mammal, preferably a human.
  • d isorders that may be treated with a compound of the invention include cognitive-related disorders and disorders associated with neuropathic pain.
  • the invention relates to a method of treating a cognitive-related d isorder comprising administering a therapeutically effective amount of a compound of the invention to a patient in need thereof.
  • This invention also relates to a method of treating a disorder or cond ition selected from psychosis, -schizophrenia , cond uct disord er, d isruptive behavior d isorder, bipolar d isorder, psychotic episod es of a nxiety, anxiety- associated with psychosis, psychotic mood disorders such as severe major depressive d isorder; mood d isord ers associated with psychotic d isorders such as acute mania or depression associated with bipolar d isorder and mood d isorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct d isorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement d isorders associated with Parkinson's disease, tard ive dyskinesia and other d rug induced and neurodegeneratson based d yskinesias; attention deficit hyperactivity disorder, cognitive d isorders such as dementias (including age related dementia, and s
  • the invention relates to a metho ⁇ of treating a d isorder or condition selected from psychosis , schizophrenia , bipola r disorder, psychotic episodes of anxiety, anxiety associated with psychosis , psychotic mood disorders such as severe major depressive disorder; mood d isorders associated with psychotic d isorders such as acute ma nia or depression associated with bipolar disorder and mood d isorders associated with schizophrenia, cognitive d isorders such as dementias (including age related dementia, and senile dementia of the Alzheimer's type), memory d isord ers and any combination thereof.
  • a d isorder or condition selected from psychosis , schizophrenia , bipola r disorder, psychotic episodes of anxiety, anxiety associated with psychosis , psychotic mood disorders such as severe major depressive disorder
  • mood d isorders associated with psychotic d isorders such as acute ma nia or depression associated with bipolar disorder
  • mood d isorders associated with schizophrenia cognitive d isorders such as dementias (including
  • the compounds of the invention are useful for a treating child hood learning d isorders such as Developmental a rticulation d isorder.
  • Developmental expressive language d isorder Developmental receptive language disorder.
  • Developmental reading d isorder (such as dyslexia).
  • Developmental writing disorder Developmental arithmetic disorder and Attention d isorders (such as ADH D),
  • the compounds of the invention are useful for treating benign forgetfuiness .
  • the invention relates to a method of treating a d isorder associated with neuropathic pain comprising ad ministering a therapeutically effective amount of a compound of the invention to a patient in need thereof.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the d isord er or cond ition to which such term applies, or one or more symptoms of such d isorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • treating aiso includes adjuvant and neoadjuvant treatment of a subject.
  • Neurode pain refers to pa in , typically chronic in d uration, initiated or caused by a primary lesion or dysfunction in the nervous system .
  • Nerve damage can be caused by trauma and d isease and thus the term 'neuropathic pain' encompasses many d isorders with d iverse etiologies.
  • peripheral neuropathy include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia , back pain, cancer neuropathy, H IV neuropathy, pha ntom limb pa in , carpal tunnel synd rome, central post-stroke pa in and pain associated with chronic alcoholism , hypothyroid ism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency.
  • Neuropathic pain is pathological as it has no protective role. It is often present well after the original ca use has d issipated , commonly lasting for yea rs, significa ntly decreasing a patient's quality of life.
  • neuropathic pain include spontaneous pain, which can be continuous, and paroxysma l or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus), ailodynia (sensitivity to a normally innocuous stimulus), shooting burning pain, and tingling a nd numbness.
  • hyperalgesia increased sensitivity to a noxious stimulus
  • ailodynia sensitivity to a normally innocuous stimulus
  • shooting burning pain and tingling a nd numbness.
  • the diagnosis of neuropathic pain generally requires a complete med ical history that includes a careful description of symptoms and a physical examination .
  • the in vitro activity of the compounds of the invention may be determined by the following proceed ures. D AAO;
  • DAAO assays are known in the literature.
  • One DAAO assay that can be used to demonstrate the activity of the compound s of the invention is based on the measurement of H5Oj1 one of the products of the action of DAAO on the amino acid substrate of interest, serine.
  • Amplex Red f nvitr ⁇ gen Life Science # A- 1 2222
  • Amplex Red f nvitr ⁇ gen Life Science # A- 1 2222
  • Resor ⁇ fin horseradish peroxidase
  • i nhibitor compound s are d iluted in 100% DMSO starting at 4 mM in half log increments to create an 1 1 -point dose response by the Pfizer Material Management Group.
  • Each d ilution is spotted in d uplicate, 0,5 microliters/well, into black 384 well plates (Costar #3573).
  • No inhibition control wells ZPE are spotted with 0.5 microliters of 100% DMSO and 1 00% inhibition control wells (H PE) are spotted with 0.5 microliters of 4 mM 3-hydroxyquinolin-2(1 H)- one in 1 00% DMSO.
  • assay buffer (10OmM Tris-HCL, pH 8.5) containing 4 nM human DAAO enzyme expressed in sf ⁇ insect cells (produced and purified in-house), 80 uM flavin adenine d inucleotide (Sigma #F8625), 0.8 units horserad ish peroxidase (Sigma #P8250), and 100 uM Amplex Red (Molecular Probes #A12222) were added to each well of the plate using a Titertek MuitiDrop-384 reagent addition device, Next, twenty microliters of assay buffer containing 200 uM D-Serine (Sigma #84250) was added using the M ⁇ itiDrop.
  • the plates are spun at 1 ,000 rpm to ensure ail liquid is coalesced to the bottom of the well. Exposure of Amplex Red to light must be kept to a minimum . The reaction is then incubated in the dark at ambient temperature for 30 - 60 minutes before read ing the plates on a PerkinElmer Envision 21 03 M ⁇ itiiabe! Reader using the following settings: 1 0 flashes of the flash lamp, excitation filter 530 nm, emission filter 590 nm. The mean of the plate HPE and ZPE control values a re used to calculate % inhibition values for each compound well in SIGHTS (an in-house data analysis software package) and non-linear curve fitting is used to calculate an IC50 value for each compound .
  • SIGHTS an in-house data analysis software package
  • the compounds of this invention can be ad ministered via either the oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topicai routes to mammals.
  • these compounds are most desirably administered to humans in doses ranging from about 1 mg to about 2000 mg per day, although variations will necessarily occur depend ing upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of from about 0 1 mg to about 20 mg per kg of body weight per day is most desirably employed .
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day.
  • the pharmaceutical composition may, for example, be in a form suitable for oral ad ministration such as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension: for parenteral injection such as a sterile solution, suspension or emulsion; for topical ad ministration such as an ointment or cream; or for rectal administration such as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pha rmaceutical compo sition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingred ient, in addition, it may include other med icinal or pharmaceutical agents, carriers, adjuvants, etc.
  • the pharmaceutical composition of the invention is in a form suitable for oral administration.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered , if desired .
  • Suitable pharmaceutical carriers include inert d iluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired , contain add itional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • various disi ⁇ tegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate. sod ium lauryl sulfate and talc a re often useful for tabieting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and , if desired , emulsifying agents or suspend ing agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • M ethods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences M ack Publishing Company, Easter, Pa., 1 5th Ed ition ( 1375).
  • the compounds of the invention may be ad ministered in combination with one or more add itional medicinal or pharmaceutical agents ("the additional active agent").
  • the additional active agent Such use of compound s of the invention in combination with an add itional active agent may be for simulta neous, separate or sequential use.
  • the compounds of this invention are administered as adjunctive therapy with antipsychotics such as Ziprasidone (Geodon), molindone, loxapine, risperidone, olanzapine, quetiapine, aripiprazole, paliperidone, 2yrrexa, bifeprunox, vabicaserin, ispronicline, sertindole, amisulpride, prochlorperazine, fluphenazine, trifluoroperazine, thioridazine, haioperidoi, chioropromazine, flupentixoi, pipotiazine, clozapine, ana pimozide.
  • antipsychotics such as Ziprasidone (Geodon), molindone, loxapine, risperidone, olanzapine, quetiapine, aripiprazole, paliperidone, 2yrrexa, bif
  • the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyi, L-dopa , Requip, Mirapex, MAOB inhibitors such as seiegine a nd rasagiiine, com P inhibitors such as Tasmar.
  • CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyi, L-dopa , Requip, Mirapex, MAOB inhibitors such as seiegine a nd rasagiiine, com P inhibitors such as Tasmar.
  • ⁇ .2 ⁇ inhibitors COX-2 inhibitors, gaba pentenoids, pr ⁇ pentofylline or metryfonate, and antipyschotics such as PDE1 0 inhibitors, 5HT2C agonists , a lpha 7 nicotinic receptor agonists, CB 1 antagonists and compounds having activity antagonizing dopamine D2 receptors.
  • antipyschotics such as PDE1 0 inhibitors, 5HT2C agonists , a lpha 7 nicotinic receptor agonists, CB 1 antagonists and compounds having activity antagonizing dopamine D2 receptors.
  • the compounds of the invention are administered as adjunctive therapy with Alzheimer's thera peutics includ ing donepezil, rivastigmine, galantamine, memantine; d imebon, immunotherapeutics (such as bapineuzumata. LY 2062430.
  • the one or more add itiona l active agents when used , are administered prior to administration of the compounds of the invention.
  • the one or more add itional active agents when used , are administered after administration of the compounds of the invention.
  • the one or more additional active agents when used , are ad ministered at about the same time as administration of the compounds of the invention-
  • the additional active agent may be administered by any route useful to administer said add itional active agent I
  • the one or more additional active agents are present in the pharmaceutical composition of the invention.
  • the invention relates to a method of treating a patient with a pharmaceutical composition of the invention further comprising one or more additional active agents. T he examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.
  • a ll patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entireties.
  • Step 1 6-Fluoro-1H-indo!e-2,3-dione (6-fluoroisatin, 200 mg, 1.2 mMoi), diethylamide (0.24 ml. 2.3 mMol), and ethyl diazoacetate (0,24 mL 2.3 mMol) were dissolved in ethanoi (15 mL) and stirred at room temperature for 64 hours.
  • Step 2 Methanol (7.5 ml), water (7.5 ml) and the compound from step 1 (100 mg, 0.4 mMoi) were combined in a 30 mL microwave tube and treated with lithium hydroxide (86 mg, 3.6 mMol), The reaction was subjected to microwave conditions (Biotage Advancer, 15O0C, high power) for 2 hours, with 30 seconds of prestir ⁇ ng. A white solid was removed via filtration, and the filtrate was acidified to pH 0 with 1N hydrochloric acid. Filtration of the resulting precipitate provided the title compound as a beige solid (70 mg, 0.39 mMoi). MS (APCI) m/z 180.0 (M+1).
  • Step 1 Ethyl 5-chloro-64luor ⁇ -3-hydroxy-2-o ⁇ o-1,2-d!hydroqumol ⁇ ne- 4-carboxy!ate was prepared according to the genera! procedure for the synthesis of intermediate in Step 1 of Example 1, except that 4-chloro-5- fluoro-1H-indole-2,3-dione was used in place of 6-f!uor ⁇ -1H-indo!e-2,3-di ⁇ ne, and that the acfueous filtrate after the hydrochloric acid treatment was extracted with dichloromethane (2 x 15 rnL) and the combined organic layers concentrated in vacuo to provide additional aliquots of intermediate (total: 220 mg.0.77 mMol, 77%). LCMS m/z 284,1 (M-1).
  • Step 2 The title compound was prepared according to the general procedure for the synthesis of Example 1 , except the microwave reaction was carried out for 5 hours, to provide the title compound as a beige solid (9 mg, 0042 mMol, 9%).
  • Step 1 Preparation of ethyl 7-ethyl-3-hydroxy-2-oxo-1 ,2- dihydroq ⁇ ino! ⁇ ne-4-carboxylate.
  • 6 -Ethyl-1H- ⁇ dole-2.3-d ⁇ one (200 mg, 1.1 mMol), di ⁇ thylamin ⁇ (0.24 mL 2.3 mMol), and ethyl diazoacetate (0,24 mL.2.3 mMol) were dissolved in ethanol (15 ml) and stirred at room temperature for 64 hours.
  • Step 1 Preparation of 4-fiuoro-3-methoxyquinoiin-2(1H)-one.
  • T he general method of A. S. Kiselyov et a!.. Organic Letters, 2004, 6, 4061 was employed to prepare the title compound.
  • Ethyl methoxyacetate (0,59 ml, 5.0 rnfvioi) was added to a freshly prepared solution of lithium diisopropylamide (13 mMol) in tetrahydrofuran (5 mL) at -780C.
  • 2-(trif!uoromethyl)aniline (0.15 ml, 1.2 mMol) was added and the reaction mixture was allowed to warm to room temperature and stir for 16 hours.
  • Step 1 Preparation of 4,8-difluoro-3-methoxyquinolin-2(1 H)-one, 4,8-Difluoro-3-methoxyqu ⁇ nolin-2(1H)-one was prepared according to the general procedure for the synthesis of the intermediate in Step 1 of Example 4. except that 2-fl ⁇ oro-6-(trifluoromethyi)aniline was used in place of 2-(trifluoromethyl)sni!ine. 4t8-Difluoro-3-methoxyquinolin-2(1H)-one was obtained as an off-white, fluffy solid (9 mg, 0.043 mMol, 3%), LCMS m/z 212.1 (M+1).
  • Step 2 The title compound was prepared according to the general procedure for the synthesis of product in Example 4, except that 4,8-difluoro-
  • Ethyl methoxyacetate (0.71 rnL, 8.0 mMol) was added to a -780C solution of lithium bis(trimethy!silyl)amide (1.0 M solution in tetrahydrofuran, 6.0 mL, 8.0 mMol) in tetrahydrofuran (6 mL).
  • a solution of 3- arninopyridine-2-carbaidehyde (244 mg, 2.00 mMol) in tetrahydrofuran (3 mL) was added drop-wise from a syringe.
  • the resulting light orange solution was allowed to come slowly to room temperature as the dry ice/acetone bath warmed up.
  • Step 2 In a microwave vial equipped with a stir bar, finely ground product from Step 1 (10 mg, 0,06 mMol) was mixed with anhydrous dichloromethane (1 mL) and cooled in a dry ice/acetone bath. After addition of boron trifar ⁇ mid ⁇ (1.0 M solution in dichl ⁇ romethane, 0.38 mL.0,38 mMol), the reaction was left in the cold bath for 5 minutes, then stirred at room temperature for 20 minutes, and finally heated in a microwave reactor for 10 minutes at 1000C. The tightly capped reaction was then subjected to conventional heating at 6O0C for 65 hours.
  • boron trifar ⁇ mid ⁇ 1.0 M solution in dichl ⁇ romethane, 0.38 mL.0,38 mMol
  • Step 1 Preparation of 3-methoxy-1 ,7-naphthyridin-2(1 H)-one.
  • 3-Methoxy-1,7-naphthyridin-2(1tf)-one was prepared according to the genera! procedure for the synthesis of the intermediate from Step 1 of Example 8, except that 3-aminoisonicQtinaldehyde was used in place of 3- aminopyridine-2-carbaidehyde.
  • Product was obtained as white and light yellow solids (88 mg, 0.50 mMol, 25%), LCMS m/z 175,1 (M-"! ).
  • Step 2 The product from Step 1 (10.9 mg. 0.062 mMol) was mixed with anhydrous dichlor ⁇ methan ⁇ (2 ml) and cooled in a dry ice/acetone bath. After addition of boron tribromide (1.0 M solution in dichloromethane.0.32 mL. 0.32 mMol), the reaction was left in the cold bath for 30 minutes, then allowed to warm to room temperature and stir for 18 hours. The reaction was cooled to -78°C again, and additional boron tribromide (1 mL, 1 mMol) was added. The mixture was allowed to reach ambient temperature, and stirred for 7 days; after which it was cooled in an ice bath and quenched with methanol (4 mL).
  • methanol 4 mL
  • Ethyl methoxyacetate (0,71 mL. 6.0 mMol) was added to a -780C solution of lithium bis(trimethy!silyl)amide (1.0 M solution in tetrahydrofuran, 6.0 mL, 6,0 mMol) in tetrahydrofuran (6 mL).
  • a solution of 4- arninonicotinaidehyde (244 mg, 2.00 mMol) in tetrahydrofuran (4 ml) was added drop-wise from a syringe. The resulting light orange solution was allowed to come slowly to room temperature as the dry ice/acetone bath warmed up.
  • Step 2 3-Methoxy-1,6-naphthyridin-2(1H)-o ⁇ e from Step 1 (25 mg, 0.14 mMol) was mixed with anhydrous dichloromethane (2 mL) and cooled in a dry ice/acetone hath. After addition of boron tribromide (1,0 M solution in dichloromethane, 0.57 mL, 0,57 mMol), the reaction was left in the cold bath for 30 minutes, then allowed to warm to room temperature and stir for 18 hours.
  • Step 1 Preparation of 5-methoxy-1 -methyl- 1,7-dihyd r ⁇ -6H- pyra2o!o[3,4-6]pyriclfin-6-one.
  • Ethyl methoxyacetate (0.35 ml, 3,0 rriMoi) was added to a -780C solution of lithium bis ⁇ t ⁇ methyisilyl)amide (1.0 M solution in tetrahydrofuran, 3.0 mL, 3.0 rnMol) in tetrahydrofuran (3 ml_).
  • a solution of S- am ⁇ no-1-m ⁇ thyl-1H-pyrazole-4-carbaidehyde 125 mg, 1.00 mMolj in tetrahydr ⁇ furan (3 mL, necessary to warm this to achieve a solution was added drop-wise from a syringe.
  • Step 2 5-Methoxy-1 -methyl- 1 ,7-dihydrQ-6H-pyra2 ⁇ lo[3,4-£>]py ⁇ din-S- one from Step 1 (32 mg, 0.18 mMol) was mixed with anhydrous dichloromethane (2 mL) and cooled in a dry ice/acetone bath. After addition of boron tribromide (1.0 M solution in dichloromethane, 0.72 ml, 0.72 mMol), the reaction was left in the cold bath for 15 minutes, then allowed to warm to room temperature and stir for 18 hours. It was then cooled to -7S0C and quenched with methanol (5 mL).
  • Step 1 Preparation of 3-aminothi ⁇ phene-2-carbaldehyde.
  • Step 2 Preparation of 6-methoxythieno[312-6]pyridin-5(4H )-one.
  • E thyl methoxyacetate (2.7 ml, 23 mMol) was added to a -780C solution of lithium bis(trimethylsilyi)amide (1 .0 M solution in tetra hyd rofuran , 23.0 ml, 23.0 mMol).
  • a solution of 3-aminathioph.ene-2-carbaldeh.yde (480 mg, 3.8 mMol) in tetrahyd rofuran (10 ml) was added , a nd the resulting dark brown mixture was allowed to come slowly to room temperature.
  • reaction mixture was purified by silica gel chromatography (Eluant: ethyl acetate, then 10% methanol in ethyl acetate, then 1 5% methanol in ethyl acetate).
  • the material obtained from this column was titurated with 10% methanol in DCM and then filtered to provide 8- methoxythieno[312-fc]py ⁇ d!n-5(4H )-one as a brown solid ⁇ 12 mg, 0.066 mMol).
  • 1 H NMR 400 MHz, CDCb with 2 drops CD3OD) .5 3.88 (S, 3H ), 7.03 (d .
  • Ethyl 8-f!uoro-3-hydroxy-2-oxo-1 ⁇ -dihycJro ⁇ uinoline- ⁇ -carboxylate was prepared according to the general procedure for the synthesis of the intermediate of Step 1 of Example 1. except that 7-fluoro-1H-indole-2,3-dione was used in place of 6-fiLi ⁇ ro-1H-i ⁇ G ⁇ ie»2,3-dione. Ethyl 8-fluoro-3-hydroxy-2- oxo-1.2-dihydroquinoline-4-carboxylate was obtained as an orange solid (1.03 g, 4.1 mMol, 68%). LCMS m/z 250.1 (M-1).
  • 3-Hydroxy-7-methylquinolin-2(1H)- ⁇ ne was prepared according to the genera! procedure for the synthesis of the intermediate of Step 1 of Example 11, except that ethyl 3-hydroxy-7-m ⁇ thyi-2-oxo-1,2-dihydroquinoli ⁇ '4- earfa ⁇ xyiate [see MJ. Fray et a!., Medicinal Chem. Research 1996, 6, 581] was used in place of ethyl 8-fl ⁇ oro-3-hydroxy-2-oxo-1s2-dihydfoquinoline-4- carboxyiate. The title compound was obtained as a tan solid (49 mg, 0,28 mMol, 88%).
  • Step 1 Ethyl 7-chioiO-3-hydroxy-8-methy!-2-oxo-1,2-dihydroquino!ine- 4-carboxylate.
  • Ethyl 7-chl ⁇ rQ-34iydrOxy-8-methyJ-2 ⁇ )xo-1.2 ⁇ !hyd!Oquinolin ⁇ -4- carboxylase can be prepared according to the procedure of MJ. Fray et a!.. Medicine! Chem Research 1996, 6, 581 and was obtained as a beige solid.
  • Step 2 The title compound was prepare ⁇ according to the general procedure for the synthesis of Example 12, except that ethy! 7-ch!oro-3- hydroxy-8-methy!-2-oxo-1,2-dihydroquinoline-4-carboxy!ate was used as the starting material. The title compound was obtained as an off-white solid.
  • CD1OD ⁇ 2.49 (S13H)16.76 fs, 1H), 7.09 (d, J ⁇ B ⁇ Hz, 1H), 7.16 (d, >8.6 Hz,
  • the beige precipitate was filtered, then resuspended in 1N hydrochloric acid and heated at reflux for about 66 hours.
  • the cooled reaction mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate.
  • Step 3 Preparation of ethyl ⁇ 2Z)-3-(3-amino-2-furyl)-2- methoxyacryiate.
  • a solution of lithium aluminum hydride (1.0M solution in tetrahydrof ⁇ ran, 18 mL, 18 mmoi) was cooled in an ice bath, and treated drop- wise with a solution of 2-amino-6-f! ⁇ orobenzoic acid (2.00 g, 12.9 mrnol) in tetrahydrofuran (30 mL).
  • the ice bath was allowed to melt over the following 18 hours and the reaction mixture warmed to about 250C.
  • the reaction was then quenched by the addition of sodium sulfate cieca hydrate (2 g) and saturated aqueous sodium chloride solution (6 mL). The resulting mixture was stirred for 1.5 hours, and then filtered through Celite.
  • 2-Amino-6-methylb ⁇ nzaldehyde was prepared according to the general procedure for the synthesis of Example 19, except that 2-amino-6- methylbenzaldehy ⁇ e was used as the starting material. The solid obtained in this way was recrysta ⁇ hzed from heptane, to afford 2-amino-6- methylbenzaldehyde as bright yellow crystals. Yield; 258 mg, 1.89 mmol, 52%.
  • Step 4 Preparation of compound 3-hydroxy-5-rnethylquinolin-2(1W)- one.
  • T he title compound was prepared according to the genera! procedure for the synthesis of Example 10, except that 3-methoxy-5-methylqu ⁇ nolin- 2(1H)-one was used as the starting materia!.
  • Step 1 Preparation of 5-chloro-3-methoxyquinoiin-2(1H)-one. 4 -Ch! ⁇ ro-1H-indole-2,3-dione (182 mg, 1.00 mmol), diethylamine (0.207 ml, 2.0 mmol ⁇ , and (thmethyl$ilyl)dlazomethane (2M solution in hexanes, 1.0 mL, 2.0 mmol ⁇ were dissolved in ethanol (5 mL) ana stirred at about 250C for about 18 hours.
  • the titie compound was prepared from 2-am ⁇ no-5-bromo-3- pyridin ⁇ carboxaldehyde using the procedure described in Example 8. APC! m/z 239 (M-1). 1H NMR (400 MHz, DMSO) ⁇ 12.57 (s, 1H), 10.11 (S, 1H), 8.37 (s, 1H).8.20 (s, 1H).7.01 (S. 1H).
  • Step 1 Preparation of 8-iodo-3-methoxyquin ⁇ lin-2(1H)-one.
  • 8 -fodo-3-methoxyqi!inolin-2(1H)-one was prepared from 7-iodo-1H- indo!e-2,3-clione using the same procedure as described in step 1 of Example 21.
  • 1H NMR (400 MHz, CD3OD) S 7.87 (m, 1 H), 7.62 (m, 1H), 7.21 (m, 1H), 6.99 (m, 1H), 392 (S13H).
  • Step 2 Preparation of 3-methoxyquinolin-2(1H)-one-8-carbon ⁇ trile. 8 -iodo-3-methoxyquinolin-2(1W)-one (90mg, 0.30 mmoi), zinc cyanide (41.8 mg, 0.356 mmol), xanthphos (3.50 rng: 0.0060 mmol), Pd2(dba)3 (2.80 mg; 0.0180 mmol) and TMEDA (14,5 mg, 0.125 mmol) were loaded into a 10 mL microwave tube (under nitrogen) with a stirring bar.
  • T he title compound was prepared from 4-chloro-6-f!uoro-1H-i ⁇ dol ⁇ -2:3- dione using the procedure described in Example 21, step 1, except that only 0.8 equivalents of the TMS diazomethane reagent was added to the reaction mixture. The product was taken up into alcohol and treated with 1N HCI in dioxane and then concentrated to give the title compound as a hydrochloride salt.
  • 1H NMR (400 MHz. DMSO) ⁇ 12.27 (S1 1H), 10.03 (S1 1H): 7.27 (m, 1H), 7.16 (s, 1H), 6.39 (m, 1H),
  • the compounds of Table 1 may be prepared according to methods analogous to those described above for Examples 1-37.

Abstract

La présente invention concerne des hydroxyquinolin-2(1H)-ones connues et nouvelles et leurs dérivés, pouvant être employés dans le traitement de troubles de type cognitif et de troubles de type douleur névropathique chez un mammifère, par exemple un humain. La présente invention concerne également des compositions pharmaceutiques incluant de tels composés.
PCT/IB2009/054925 2008-11-18 2009-11-05 Hydroxyquinolin-2(1h)-ones et leurs dérivés WO2010058314A1 (fr)

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WO2014074926A1 (fr) * 2012-11-09 2014-05-15 Rutgers, The State University Of New Jersey Hydroxyquinolones thérapeutiques
JP2014520790A (ja) * 2011-07-07 2014-08-25 武田薬品工業株式会社 統合失調症、認識障害及び疼痛などの疾患の治療におけるｄ−アミノ酸オキシダーゼ（ｄａａｏ）阻害剤としての、５−又は６−置換３−ヒドロキシ−２（１ｈ）−ピリジノン
JP2014522830A (ja) * 2011-07-07 2014-09-08 武田薬品工業株式会社 ピリミジノン化合物およびそれらの使用
JP2014524461A (ja) * 2011-08-22 2014-09-22 武田薬品工業株式会社 ピリダジノン化合物、及びｄａａｏ阻害剤としてのその使用
JP2016502998A (ja) * 2012-12-17 2016-02-01 武田薬品工業株式会社 Ｄａａｏ酵素阻害剤としてのピリダジノン
US9505753B2 (en) 2012-08-08 2016-11-29 The Johns Hopkins University Inhibitors of D-amino acid oxidase
CN106608824A (zh) * 2015-10-21 2017-05-03 复旦大学 芳酸酯类化合物及其制备方法和用途
WO2017133752A1 (fr) * 2016-02-04 2017-08-10 Merck Patent Gmbh Composés [1,5]-naphthyridine et polymères utilisés comme semi-conducteurs
JP2019006804A (ja) * 2014-10-06 2019-01-17 日本曹達株式会社 ３−アリールオキシキノリン誘導体の製造方法
US10202399B2 (en) 2011-11-15 2019-02-12 Takeda Pharmaceutical Company Limited Dihydroxy aromatic heterocyclic compound
WO2019043635A1 (fr) 2017-09-01 2019-03-07 Richter Gedeon Nyrt. Composés inhibiteurs de l'activité de d-amino acide oxydase
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
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US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

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JP2014522830A (ja) * 2011-07-07 2014-09-08 武田薬品工業株式会社 ピリミジノン化合物およびそれらの使用
US9931340B2 (en) 2011-08-22 2018-04-03 Takeda Pharmaceutical Company Limited Pyridazinone compounds and their use as DAAO inhibitors
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